There are enormous species differences in the acute toxicity for TCDD and its structural analogs such as the polychlorinated dibenzofurans (PCDFs) These compounds appear to exert their effects in in vivo and in vitro systems through a mechanism requiring the Ah receptor. TCDD is a potent hepatocarcinogen in female rats but not male rats. Our studies focused on potential mechanisms for the observed sex specificity by evaluating histological and biochemical parameters in a two-stage model for hepatocarcinogenesis in female rats using diethylnitrosamine (DEN) as the initiating agent and TCDD as the promoting agent. Increases in preneoplastic foci were detected in intact rats and to a lesser extent in ovariectomized rats. This finding was consistent with the cell proliferation data which demonstrated that TCDD markedly increased the labelling index of hepatocytes only in intact rats. These data suggest that ovarian hormones (probably estrogens) play a significant role in the hepatocarcinogenic actions of TCDD. Dose-response relationships for effects of TCDD on receptor pathways important to regulation of cell division are being evaluated in the rat tumor promotion model. Results revealed that effects on epidermal growth factor receptor and estrogen receptor correlated with tumor promotion but induction of cytochrome P-450 isozymes did not. In order to address the issue of human sensitivity to the effects of TCDD and PCDFs, we have examined placentas from humans exposed to PCDFs in Taiwan and compared biochemical changes in human placenta to those occurring in rats. Our data reveal that humans are a sensitive species to PCDFs based on enzyme induction and effects on EGFR. Current studies are using rat, mouse and human lymphocyte samples to better characterize species differences in response to TCDD exposure . Other studies are investigating the mechanistic bases for interindividual variation in responsiveness to TCDD.